Many drugs have cardiotoxic side effects, e.g. arrhythmias or negative effects on the contractive capacity of the heart muscle. Over the last years it has become evident that a common side-effect of a number of drugs is a prolonging effect on the QT interval in the cardiac cycle, which is an important cause of drug-induced life threatening arrhythmias. For instance, during the past years, the development of several drugs has been aborted in late phases of preclinical testing or clinical trials, and even post-marketing due to undesirable effects on the QT interval of the surface electrocardiogram (ECG). A prolongation of this interval to more than 440 to 460 msec may allow life threatening arrhythmias, e.g. torsade de pointes (TdP), to occur and has been associated with a wide variety of drugs.
This was acknowledged in 1998 when the Food and Drug Administration (FDA) defined prolongation of the QT interval as a major drug safety issue. Subsequently, identification of QT prolongation and clinical torsade de pointes has led to the removal of several drugs from the market in the United States, including terfenadine, astemizole, thioridazine, and grepafloxacin, while many others have been required by the FDA to carry additional safety labeling warning of the potential risk. Currently, assessing risk for delayed ventricular repolarization and QT interval prolongation is part of the standard non-clinical evaluation of NCE's as adopted by the FDA and EMEA for all drugs in development.
Unfortunately, currently available preclinical in-vitro cell-based model systems to test for cardiotoxicity are inadequate for detecting the majority of these side-effects, while predictive in-vivo animal studies are very expensive, as well as ethically challenged. In addition, cardiotoxicity results obtained from animal studies cannot be easily extrapolated to humans.
The testing process is further complicated by the fact that these cardiotoxic effects of drugs may only become apparent during actual cardiac muscle stretching and contraction as occurs in vivo in the beating heart, especially during (strenuous) physical exercise; and in cardiac diseases, for example diseases associated with cardiac overload, e.g. heart failure, and diseases characterized by inflammation, like during influenza infections. Currently no testing model systems exist that simulate a normal beating heart, in either a physiological situation, i.e. a stretch-contraction cycle, or a pathophysiological situation, such as excessive stretch/contraction against increased pressure, associated with cardiac failure. Moreover, different drugs can have different negative effects on the heart function.
Some human cell-based model systems are available for cardiotoxicity testing. These model systems typically may consist of cardiomyocytes, either animal or human, and either primary cardiomyocytes or stem cell-derived cardiomyocytes on standard multi-electrode arrays (MEA), as disclosed in “Pluripotent stem cell lines” J. Yu and J. A. Thomson, Genes Dev. 2008, 22, p. 1987-1997. However the usefulness of these systems is constrained by the fact that these are static model systems not taking into account the dynamics of the beating heart.
In ‘An Electro-Tensile Bioreactor for 3-D Culturing of Cardiomyocytes’ by Zhonggang Feng et al. in IEEE Engineering in Medicine and Biology Magazine, July/August 2005, pages 73-79, a bioreactor is disclosed which allows for the in-plane stretching of a cardiomyocyte-containing gel layer disposed on a stretchable silicone plate to simulate the mechanical and electrical response of the myocardium in vivo. A drawback of this device is that it is quite complex and not particularly suitable for cardiotoxicity testing due to the fact that the cardiomyocytes are embedded in a gel.